Research ArticleImmunotherapy

Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies

Science Translational Medicine  06 Jan 2016:
Vol. 8, Issue 320, pp. 320ra3
DOI: 10.1126/scitranslmed.aad5222

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Young blood for immunotherapy

Adoptive cell therapies with engineered T cells have shown promising results in patients whose cancer is recalcitrant to other therapies. However, chemotherapy can inhibit both the expansion and function of T cells, limiting the success of this approach. Now, Singh et al. report that T cell populations enriched for early lineage cells expanded better in vitro. These cells could be specifically enriched by collecting T cells at time points diametric to chemotherapy administration and expanded in vitro with targeted culture methods. These data suggest that enriching early lineage cells may increase the number of patients who may benefit from engineered T cell therapy.

Abstract

Engineered T cell therapies have begun to demonstrate impressive clinical responses in patients with B cell malignancies. Despite this efficacy, many patients are unable to receive T cell therapy because of failure of in vitro expansion, a necessary component of cell manufacture and a predictor of in vivo activity. To evaluate the biology underlying these functional differences, we investigated T cell expansion potential and memory phenotype during chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). We found that patients with T cell populations enriched for early lineage cells expanded better in vitro and that patients with ALL had higher numbers of these cells with a corresponding enhancement in expansion as compared to cells from patients with NHL. We further demonstrated that early lineage cells were selectively depleted by cyclophosphamide and cytarabine chemotherapy and that culture with interleukin-7 (IL-7) and IL-15 enriched select early lineage cells and rescued T cell expansion capability. Thus, early lineage cells are essential to T cell fitness for expansion, and enrichment of this population either by timing of T cell collection or culture method can increase the number of patients eligible to receive highly active engineered cellular therapies.

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